There is a need for monitoring the effectiveness of a disease treatment, particularly for diseases where the condition of the patient can deteriorate rapidly if the treatment is not effective. One such disease is cancer, particularly, metastasis of cancer, which involves angiogenesis. Angiogenesis, which is formation of new blood vessels from preexisting ones, is known to be important for tumor growth and metastasis. Without blood supply, tumor growth is diffusion-limited, and is generally restricted to less than 1 mm3 to 2 mm3. The recruitment of a vascular supply allows a tumor to grow beyond this limited volume and provides a route for metastasis. Angiogenesis supplies oxygen and nutriments needed for tumor growth.
Typically, the angiogenesis process takes place as follows. The diseased tissue produces and releases angiogenic growth factors (proteins) that diffuse into the nearby tissues. The angiogenic growth factors bind to specific receptors located on the endothelial cells of nearby preexisting blood vessels. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules including enzymes. Enzymes form tiny openings in the sheath-like covering (basement membrane) surrounding all existing blood vessels. The endothelial cells begin to divide (proliferate), and they migrate out through the openings of the existing vessel towards the diseased tissue (tumor). Specialized molecules called adhesion molecules, or integrins (αvβ3, αvβ5), serve as grappling hooks to help pull the sprouting new blood vessel sprout forward. Additional enzymes (matrix metalloproteinases or MMP) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel. Sprouting endothelial cells roll up to form a blood vessel tube. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood. The newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow begins.
In angiogenesis, the neoplastic cells can recruit, in addition to normal endothelial cells, the macrophages, fibroblasts, mast cells, and/or platelets to generate new vessels from pre-existing ones at the periphery of the tumor. Angiogenesis is thus orchestrated by a web of signaling pathways controlled by proangiogenic protein signaling molecules. The proangiogenic signaling molecules arise from the tumor and react with the cells in the surrounding normal tissue (paracrine molecules). The proangiogenic signaling molecules are generated from cells in the normal surrounding tissue reacting with adjacent, non-neoplastic cells, and reacting with matrix of the tissue (juxtacrine molecules). Proangiogenic signaling proteins are generated from a cell in the tissue that reacts with itself (autocrine molecules). Fisher, M. J., et al., Neuroimg. Clin. N. Am. 12, 477-499 (2002), and Ch. 9 in Molecular Basis of Medical Cell Biology, 1st ed., Fuller, G. M., et al. (Eds.) Appleton and Large (1998).
Some of the common approaches to cancer treatment (including metastasis of cancer) involve surgery, radiation therapy, and/or chemotherapy. Radiation therapy and chemotherapy are effective if they are capable of killing the tumor cells; i.e., when they act as cytotoxic agents. Typically, the response to radiation therapy or chemotherapy is monitored by magnetic resonance imaging (MRI) of the tumor, wherein a decrease in tumor size is indicative of positive response to treatment.
Angiogenesis inhibitors have been proposed for cancer treatment. For example, interrupting the signaling proangiogenic pathways interrupts the blood supply to the tumor, and thereby, stops neoplastic proliferation. The major proangiogenic signaling pathways involve growth factors, integrins/proteases, coagulation/fibrinolysis factors and inflammatory factors.
The angiogenesis inhibitors are cytostatic rather than cytotoxic; accordingly, classical signs of treatment response, e.g., decreased tumor size or decreased enhancement, commonly observed in treatments involving cytotoxic agents, may not be observed with cytostatic angiogenesis inhibitors. Accordingly, classical imaging techniques such as MRI alone may not be suitable or adequate to monitor response to a treatment involving angiogenic inhibitors.
Magnetic Resonance Spectroscopy or MRS has been proposed as a tool for obtaining information on cellular metabolism; see, for example, Norfray, J. et al., Ch. 110 in Pediatric Neurosurgery, 4th ed., McLone, D. G., et al. (Eds), W.B. Saunders Co. (2001). MRS also has been proposed for diagnosing the treatment response of tumors with cytotoxic agents; see, for example, Fulham, M. J., et al., Radiology, 185, 675-686 (1992), which discloses that brain tumor metabolism was studied with 1H MRS before and after treatment with radiation therapy. MRS permits non-invasive examination of metabolic characteristics of human cancers in a clinical environment. Accessible nuclei include 31P, 13C, 1H, and 23Na. 31P MRS contains information about energy status (phosphocreatine, inorganic phosphate, and nucleoside triphosphates), phospholipids metabolites (phosphomonoesters and phosphodiesters), intracellular pH (pH NMR), and free cellular magnesium concentration (Mg2+ f). Water-suppressed 1H MRS shows total choline, total creatine, lipids, glutamate, inositols, lactate, and the like. Negendank, W., NMR in Biomedicine, 5, 303-324 (1992).
Further, U.S. Pat. No. 6,681,132 (Katz et al.) discloses a method for determining the effectiveness of chemotherapy comprising administering a dose of a cytotoxic antineoplastic agent to a subject prior to surgical removal of a cancerous tumor, acquiring magnetic resonance data from the subject, and determining whether the treatment has affected the population of a nucleus or nuclei, particularly 23Na. Negendank, W., supra, provides a review of various studies of human tumors by MRS.
In addition, Ross, B. et al., The Lancet, 641-646 (1984) discloses monitoring response to cytotoxic chemotherapy of intact human tumors by 31P MRS; Griffiths, J. R. et al., The Lancet, 1435-36 (1983) discloses the use of 31P MRS to follow the progress of a human tumor during chemotherapy with doxorubicin; Ross, B. et al., Arch. Surg., 122, 1464-69 (1987) discloses the monitoring of chemotherapeutic treatment response of osteosarcoma and other neoplasms of the bone by 31P MRS; and Norfray, J. F. et al., J. Computer Assisted Tomography, 23(6), 994-1003 (1999) discloses an MRS study of the neurofibromatosis type 1 intracranial lesions.
While MRS is effective as a tool for monitoring treatment response, the disclosures in the art show that it has been applied to monitor the response to cytotoxic agents (radiation and chemotherapy). In many cases, a detectable change in tumor size is observed only after a significantly long period of time, for example, after treatment for a period of about 3 months or more. Such long periods of time could be harmful to the patient, especially if the treatment has not been effective or only partially effective, such as, for example, treatments involving the use of angiogenesis inhibitors; during this long period of time, tumor cells could multiply or metastasize, and lead to worsening of the patient's condition.
The foregoing shows that there exists a need for a method where an early treatment response can be monitored in diseases, especially where the treatment involves the use of one or more angiogenesis inhibitors. Accordingly, the present invention provides such a method. This and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.